Insights into the roles of carrier microstructure in adhesive/carrier-based dry powder inhalation mixtures: Carrier porosity and fine particle content.

To gain insights into complex interactions in carrier-based dry powder inhalation mixtures, we studied the relationships between the carrier microstructural characteristics and performance. We used mercury intrusion porosimetry to measure the microstructural characteristics and to also derive the air permeability of eight carriers. We evaluated the performances of inhalation mixtures of each of these carriers and fluticasone propionate after aerosolization from an Aerolizer®. We did not observe a simple relationship between the carrier total porosity and the performance. Classification of the porosity according to pore size, however, provided interesting insights. The carrier nanoporosity, which refers to pores smaller than micronized drug particles, has a positive influence on the performance. Nanopores reduce the carrier effective contact area and the magnitude of interparticulate adhesion forces in inhalation mixtures. The carrier microporosity, which refers to pores similar in size to drug particles, also has a positive influence on the performance. During mixing, micropores increase the effectiveness of frictional and press-on forces, which are responsible for breaking up of cohesive drug agglomerates and for distribution of drug particles over the carrier surface. On the other hand, the carrier macroporosity, which refers to pores larger than drug particles, apparently has a negative influence on the performance. This influence is likely mediated via the effects of macropores on the powder bed tensile strength and fluidization behavior. The air permeability better represents these effects. The inhalation mixture performance improved as the carrier air permeability decreased. Interestingly, as the carrier fine particle content increased, the carrier microporosity increased and the carrier air permeability decreased. This proposes a new mechanism for the positive effect of fine excipient materials on the performance of carrier-based inhalation mixtures. Fine excipient materials apparently adhere to the surface of coarse carrier particles creating projections and micropores, which increase the effectiveness of mixing. The data also support the mechanism of powder fluidization enforcement by fine excipient materials. The current study clearly demonstrates that the microporosity and the air permeability are key dry powder inhalation carrier performance determinants. Mercury intrusion porosimetry is a useful tool in the dry powder inhalation field; it successfully allowed resolution of carrier pores which contribute differently to the performance.